Huntington's disease (HD) is caused by expression of a mutant huntingtin (Htt) protein containing an expanded polyglutamine (polyQ) tract. The primary cellular and organ level dysfunction in HD is thought to arise directly from expression of what is generally regarded as a toxic protein. The polyQ mutation is highly pleiotropic in its toxi effects. Cells expressing mutant Htt have been shown to have defects in a diverse range of molecular functions including, but not limited to, transcription, chromatin remodeling, protein homeostasis, vesicle transport, cytoskeletal organization, cholesterol homeostasis and energy metabolism. Many of these defects have also been corroborated in whole organism models of HD such as nematodes, flies and mice. However, despite the growing number of well-documented molecular defects in HD models, it remains a challenge to distinguish between proximal effects of Htt toxicity and more distal effects that reflect downstream dysfunctions cascading from primary insults. Using a genome-scale RNAi modifier screen we identified RRAS as a novel target that influences huntingtin toxicity and turnover. In this proposal we focus on characterizing the RRAS protein, a small GTPase that regulates cell movement through the plexin/semaphorin signaling pathway. We have shown that RRAS is a potent modifier of mutant huntingtin toxicity in cell and fly models of HD. We also demonstrated that RRAS is activated in cell models of HD and that this activation is consistent with alterations in motility phenotypes associated with mutant huntingtin. Finally, we present evidence that RRAS regulates huntingtin levels by affecting its turnover. Advancing the understanding of the relationship between RRAS function and huntingtin metabolism will provide insight into a druggable target that can be used to manipulate huntingtin levels in vivo.